Regulation of insulin receptors is being studied in vivo using circulating mononuclear cells and in vitro using cultured diploid fibroblasts. Down regulation in the fibroblast has been used to detect inhibitors of insulin action in plasma from insulin resistant subjects. Investigation of monocytes and fibroblasts suggest that cells from obese subjects have more receptors, reduced insulin affinity, increased insulin degradation and decreased dowm regulation. Insulin binding to monocytes from obese glucose tolerant and intolerant subjects was the same, indicating that a source of insulin resistance distinct from the receptor is present in obese Pima subjects. Insulin receptors have been solubilized and partially purified from cultured human diploid fibroblasts and from human erythrocytes. Characterization of insulin binding to solubilized insulin receptor preparations resulted in binding affinity, pH optimum and analog specificity data similar to those for the intact cells. The binding of Multiplication Stimulating Activty (MSA) as well as insulin were measured in suspended human fibroblasts and in solubilized receptor preparations. Sephadex G-200 chromatography did not separate the two receptors, although characteriztion of the specificity of binding clearly predicts two separate binding sites.